© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
F E E D I N G R E G U L AT I O N A N D O B E S I T Y
REVIEW
Endocannabinoid control of food intake
and energy balance
Vincenzo Di Marzo & Isabel Matias
Marijuana and its major psychotropic component, ∆9-tetrahydrocannabinol, stimulate appetite and increase body weight in
wasting syndromes, suggesting that the CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are
involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral
mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy
homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.
The natural compound ∆9-tetrahydrocannabinol (∆9-THC), derived
from Cannabis sativa, is responsible for the psychotropic effects of marijuana and was used in medicine before its mechanism of action was
discovered. The anti-emetic and appetite-inducing properties of cannabis have been known for centuries, but only in the last half-century
were they assigned to ∆9-THC1. This compound, as well as its synthetic
analogue nabilone, have been prescribed to ameliorate vomiting and
nausea in cancer patients since the mid-1980s and to prevent weight
loss in AIDS patients since 1992.
However, the first receptor for ∆9-THC was fully characterized2 only
in 1990. This was a G protein–coupled membrane receptor (GPCR)—as
could be expected from the fact that ∆9-THC inhibits adenylyl cyclase
and modulates the activity of Ca2+ and K+ channels in neurons in a pertussis toxin–sensitive manner3. This first cannabinoid receptor, which
is also the most abundant GPCR in the brain, was named CB1 after
the cloning of the second cannabinoid receptor subtype, CB2, which
instead is mostly present in immune cells3. The first two endogenous
cannabinoid receptor ligands, or endocannabinoids, were discovered
in the early 1990s. N-arachidonoyl ethanolamine (anandamide)4 and
2-arachidonoyl glycerol (2-AG)5,6 are derivatives of arachidonic acid,
an ω6-polyunsaturated fatty acid, which is in turn derived from essential fatty acids and is the precursor of several other chemical signals.
Phospholipid-dependent pathways for endocannabinoid biosynthesis
were discovered, leading to the cloning of the enzymes that catalyze the
formation of anandamide and 2-AG from their direct precursors: the
N-acylphosphatidylethanolamine-selective phospholipase D and the
sn-1–selective diacylglycerol lipases, respectively7,8.
The two major endocannabinoids are rapidly hydrolyzed by the fatty
acid amide hydrolase and the monoacylglycerol lipase, respectively9,10,
to compounds that are inactive at cannabinoid receptors. The cannabinoid receptors, the endocannabinoids and the enzymes catalyzing their
biosynthesis and degradation constitute the endocannabinoid system
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio
Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
Correspondence should be addressed to V.D.M. ([email protected]).
Published online 26 April 2005; doi:10.1038/nn1457
NATURE NEUROSCIENCE VOLUME 8 | NUMBER 5 | MAY 2005
(Fig. 1). Endocannabinoids are not confined to the CNS, but rather act
as local mediators in many tissues and are produced ‘on demand’ to help
restore the levels and function of other mediators (including excitatory
and inhibitory neurotransmitters) after acute or chronic alterations of
the physiological homeostasis of the cell11.
Brain endocannabinoids control food intake
Regulation of energy intake by the cannabinoid system was initially
assumed to occur centrally. Pharmacological stimulation of CB1 receptors by systemic administration of plant or endogenous cannabinoids
stimulates eating—in the case of ∆9-THC, even in satiated animals12–14.
Pharmacological blockade of CB1 receptors by systemic administration of SR141716A (rimonabant), the first selective CB1 antagonist15,
attenuates agonists’ stimulatory effects on food intake and strongly
reduces both the consumption of palatable food (such as sweet foods)
by animals fed ad libitum and the intake of normal food, but not water,
by animals deprived of food16–19. Other CB1 antagonists exert identical
effects20,21; even a single dose of the antagonist AM251 produces an
anorectic effect lasting up to 6 d (ref. 22). Furthermore, CB1-deficient
mice consume much less food in the first hours after food deprivation23. These data, together with the established neuromodulatory role
of endocannabinoids through CB1 receptors11, suggested that the brain
endocannabinoid system controls food intake at two levels. First, it
tonically reinforces the motivation to find and consume foods with
a high incentive value, possibly by interacting with the mesolimbic
pathways involved in reward mechanisms. Second, it is activated ‘on
demand’ in the hypothalamus after short-term food deprivation and
then transiently regulates the levels and/or action of other orexigenic
and anorectic mediators to induce appetite.
The hypothesis of a dual action in mesolimbic and hypothalamic
regions was substantiated by the finding that injection of endocannabinoids into these brain areas stimulates food intake in rats24,25.
Furthermore, endocannabinoid levels vary in both the hypothalamus and the limbic forebrain (but not in the cerebellum, which is
not involved in appetite regulation) during the four phases of feeding behavior in rats. These levels are highest during food deprivation
and lowest during food consumption, as expected from endogenous
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intake of normal (not necessarily palatable)
food in pre-fed, satiated animals, similar to
what was observed with high energy (palatOrexin-1 receptor
able) food27,28. This apparent discrepancy
with earlier data23 may be explained because
the separation between hedonically driven
MAGL
2-AG
and energy deprivation–driven food intake is
not so marked. The mesolimbic regions most
+
Degradation
involved in translating motivation to eat into
action (for example, the nucleus accumbens
shell) participate in the consumption of normal food as well. Rimonabant blocks food
consumption during both the consummatory
EMT
CB1
and the appetitive phases of feeding behavior
in pre-fed animals, but does not block the pavlovian response to a palatable stimulus. This
Anandamide
2-AG
finding suggests that endocannabinoids do not
Leptin
reinforce the ability of the stimulus to elicit
an approach behavior, but instead maintain
FAAH
stimulus-induced goal-directed behaviors29.
DAGL
+
Accordingly, other authors proposed that
NAPE
stimulation of CB1 receptors may enhance
-PLD
Degradation
sn-1-Acyl-2
food palatability30.
arachidonoyl glycerol
The endocannabinoid system may influence
NArPE
food intake by regulating the expression and/
or action of several hypothalamic anoretic and
Membrane
orexigenic mediators. CB1 receptors colocalize
Leptin
Membrane
phospholipids
with corticotropin-releasing hormone (CRH)
phospholipids
in the paraventricular nucleus (PVN), with
melanin-concentrating hormone in the latω6-PUFAs
eral hypothalamus, and with pre-pro-orexin in
the ventromedial hypothalamus31,32. Genetic
Postsynaptic neuron
deletion of CB1 increases expression of CRH,
pointing to a tonic inhibition of the expression
Figure 1 The endocannabinoid system in neurons. Diet-derived ω6-polyunsaturated fatty acids (ω6PUFAs) are incorporated into membrane phospholipids, which can subsequently be metabolized
of this anoretic mediator by endocannabiinto the two major endocannabinoids, 2-AG and anandamide, by membrane-associated enzymes.
noids31. Additionally, in the PVN postsynaptic
Degradative enzymes for endocannabinoids are localized to internal membranes. Leptin signaling can
endocannabinoids retrogradely inhibit glutainfluence 2-AG biosynthesis in the hypothalamus23 and anandamide hydrolysis in T-lymphocytes64.
matergic release from presynaptic neurons,
33
CB1 is located mostly presynaptically, allowing for retrograde action of endocannabinoids. CB1
thus mediating corticosterone-induced fast
signaling affects the expression of orexigenic and anoretic mediators in the hypothalamus32. DAGL:
inhibition of CRH release in this nucleus33.
sn-1 selective diacylglycerol lipase; EMT: putative endocannabinoid membrane transporters; FAAH:
fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; NArPE: N-arachidonoyl-phosphatidylTwo preliminary reports suggest that retroethanolamine; NAPE-PLD: N-acyl-phosphatidylethanolamine–selective phospholipase D; CRH:
grade signaling by endocannabinoids released
corticotropin-releasing hormone; CART: cocaine-amphetamine–regulated transcript. Blunt-ended line
from depolarized postsynaptic neurons11 also
indicates inhibition.
inhibits presynaptic GABA release in the lateral
hypothalamus and arcuate nucleus (Y. Jo, S.C.
orexigenic mediators25. In the hypothalamus, these changes in endo- Chua and L.W. Role, Soc. Neurosci. Abstr. 47.12, 2004; T. Hentges, M.J.
cannabinoid levels seemed to be inversely correlated with the changes Low and J.T. Williams, Soc. Neurosci. Abstr. 76.1, 2004). It remains to be
that are known to occur in blood levels of the neurohormone leptin, fully determined how this retrograde signaling contributes to energy
which is pivotal in regulating the hypothalamic orexigenic and ano- intake induction by endocannabinoids. Stimulation of CB1 receptors
retic signals. Indeed, leptin decreases endocannabinoid levels in the also causes sensitization of orexin-1 receptors when the two proteins
hypothalamus, much as it does for other orexigenic mediators, and are expressed in the same cell, with possible subsequent enhancement
obese rodents with defective leptin signaling show significantly higher of the appetite-inducing action of orexins34. No co-expression of CB1
hypothalamic endocannabinoid concentrations23. It has been suggested receptors and neuropeptide Y (NPY) was found, but it seems that
that an enhanced endocannabinoid tone is also linked to enhanced endocannabinoid activation downstream of NPY mediates some of its
ghrelin levels in the bloodstream after food deprivation and may under- orexigenic effects, which, accordingly, are attenuated by pharmacologilie some of the orexigenic effects of this peptide when injected into the cal or genetic impairment of CB1 (ref. 35). In contrast, rimonabant is
rat hypothalamus—effects that are in fact blocked by antagonism at as effective an anoretic agent in wild-type as in NPY-null mice23. This
CB1 receptors with rimonabant26.
indicates that the induction of food intake by endocannabinoids is not
After fasting, the endocannabinoid system in the hypothalamus is mediated by NPY (in agreement with the lack of coexpression of CB1
transiently activated, which increases energy intake. However, recent receptors and this neuropeptide) and, additionally, that the surprisingly
findings indicate that blockage of CB1 receptors can also inhibit the normal food intake of NPY-deficient mice is not due to compensaPresynaptic neuron
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
CRH, CART
expression
586
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tion by the endocannabinoid system. Finally, CB1 receptors seem to
inhibit anorectic events downstream of melanocortin-4 receptors36.
Concerning the mesolimbic system, evidence supports the hypothesis
that endocannabinoids increase the drive to eat by enhancing dopamine
release in the nucleus accumbens shell37,38 or by synergizing with opioids through as yet undefined mechanisms18,19,39–41.
The brain endocannabinoid system seems to be very important for
controlling food intake in young rodents31 and even more in newborn
mice, where pharmacological blockade of CB1 receptors at postnatal
day 1 (PND1) leads to suppression of suckling and milk ingestion and
eventually to death42. Newborn mice lacking CB1 also ingest less milk,
but with less lethal consequences42. These observations are particularly
notable because 2-AG levels peak in rat brain at PND1 (ref. 43) and
high concentrations of 2-AG are found in milk44.
Another checkpoint at which the endocannabinoid system acts on
food intake occurs in the vagus nerve that connects the gastrointestinal
tract with medulla and brainstem nuclei involved in control of satiety.
In the rat, food deprivation enhances anandamide levels in the duodenum. Here the endocannabinoid may reduce satiety by acting on the
vagus, as suggested by the anoretic action of peripherally administered
rimonabant and by the reversal of this action following destruction of
the vagal capsaicin-sensitive nerves that also mediate cholecystokinin
(CCK)-induced satiety45. Food deprivation also enhances CB1 expression in CCK-1 receptor–expressing neurons of the rat nodose ganglion
projecting to the duodenum; renewed feeding or treatment with CCK
re-establishes low levels of CB1 receptors in these neurons46. These data
suggest that reduced endocannabinoid activity may mediate induction
of satiety by CCK; they also suggest that fasting overcomes satiety (and
possibly emesis) by elevating small intestine endocannabinoid levels
and by releasing vagal CB1 receptors from CCK inhibition, thus disinhibiting the endocannabinoid system in the vagus.
Peripheral control of energy balance by endocannabinoids
The strong evidence supporting the involvement of endocannabinoids
in controlling food intake encouraged preclinical studies on the use of
CB1 antagonists against obesity47. Rimonabant reduced food intake in
genetic models of obesity, the ob/ob and db/db mice23 and Zucker rats48.
However, the effects of CB1 blockers on food intake in these models
were transient and were significantly outlasted by the effects on body
weight48. The partial dissociation between the somehow short-lasting
anorectic effect of CB1 antagonists and their longer-lasting effects on
body weight was also observed in studies using pair-fed controls and
in a model more relevant to human obesity, the diet-induced obese
mouse, where obesity is induced by a prolonged high-fat diet. In this
model, chronic CB1 blockade produced a significant reduction of fat
mass relative to skeletal muscle mass, and an improvement of metabolic
parameters typical of obesity: a reduction in plasma levels of insulin,
leptin, non-esterified fatty acids and/or cholesterol, and an increase in
the HDL/LDL cholesterol ratio49–51. Even more notably, CB1-null mice,
when fed a normal diet from birth, are leaner than their pair-fed wildtype littermates, and have less fat mass31. After a high-fat diet, these
mice, although they consume as much food as wild-type mice, do not
become obese, nor do they develop insensitivity to insulin or leptin52.
These studies suggest that only part of the reduction of body weight
and fat mass effected by CB1 antagonists is due to their anorectic action
and that these drugs also act by counteracting a peripheral tonic action
of endocannabinoids on lipogenesis and fat accumulation. Clearly,
pharmacological or genetic blockade of CB1 must be accompanied
by increased energy expenditure, and in fact rimonabant was recently
shown to increase oxygen consumption and soleus muscle glucose
uptake in ob/ob mice53. The effect of the endocannabinoid system on
NATURE NEUROSCIENCE VOLUME 8 | NUMBER 5 | MAY 2005
lipogenesis is substantiated by the finding of CB1 receptors in white
adipocytes. In these cells, stimulation of CB1 leads to activation of
lipoprotein lipase31, whereas its blockade causes up-regulation both
in vitro and in vivo51,54 of adiponectin, a hormone crucial in reducing
the expression of enzymes involved in lipogenesis. Other peripheral
organs and tissues, in particular the liver, pancreas and skeletal muscles,
might also be involved in the control of energy balance by endocannabinoids. Indeed, stimulation of CB1 receptors in the liver and hepatocytes
increases de novo fatty acid biosynthesis by increasing the expression
of the lipogenic transcription factor sterol response element–binding
protein 1c and two of its targets, acetyl-CoA carboxylase-1 and fatty
acid synthase55. The finding that a CB1 agonist enhances the expression
of the latter enzyme also in the hypothalamus55, together with the discovery of adiponectin receptors in the PVN56, supports the concept that
endocannabinoid control of energy balance at the hypothalamic and
peripheral levels are likely to be related, cross-talking phenomena.
CB1 blockers against obesity and metabolic syndromes
The preclinical data outlined above have been confirmed in the context
of human obesity by three separate phase III clinical trials carried out
with rimonabant. The results of a 2-year study, known as Rimonabant
in Obesity (RIO)-North America, with over 3,400 patients subjected to
a mild low-calorie diet, were communicated at the 2004 American Heart
Association meeting and can be summarized as follows. A 1-year treatment with a 20 mg d–1 oral dose of rimonabant causes weight losses of
≥5% and ≥10% in over 62% and 32%, respectively, of subjects completing the study but in only 33% and 16%, respectively, of control subjects
receiving placebos. The average weight loss and waist reduction were
∼8.8 kg and 8.4 cm, versus 2.9 kg and 4 cm in placebo controls, respectively. After 1 year of treatment, the blood triglyceride levels in subjects
completing the study dropped by ∼8.5% (versus a ∼4.5% increase in
placebo controls) and HDL cholesterol levels increased by ∼17.5% (versus ∼6.3% in placebo controls). Fasting insulin levels decreased by ∼2.7
µIU ml–1 compared with controls. After randomization into placebo or
drug continuation at 1 year, subjects who were kept on rimonabant for
another year did not lose further weight but continued to significantly
increase their HDL cholesterol levels, whereas the previously treated
subjects now taking placebo slowly regained weight to become undistinguishable from the placebo-placebo group only at the end of the trial.
Results identical to those in the first year of this study were obtained
in two similar 1-year studies: the RIO-Lipids and the RIO-Europe trials. In the RIO-Lipids trials, where a high percentage of patients with
metabolic syndrome was selected, and in the RIO-Europe trials, ∼50%
of the beneficial metabolic effects were dissociated from the observed
decrease in body weight, and an increase in adiponectin levels was
observed after administration of rimonabant. The pooled data from
the RIO studies (5,580 patients) at 1 year also yielded promising results
in regard to safety: only 3.6% more rimonabant-treated subjects than
placebo-treated subjects experienced any adverse events, and only
5.9% more rimonabant-treated subjects than placebo-treated subjects
discontinued treatment as a result of adverse events. These adverse
events consisted mostly of nausea (+1.3%), diarrhea (+1.3%), dizziness
(+0.6%), depression (+1.4%) and anxiety (+0.7%), and in most cases,
subjects showed tolerance to them after the first weeks of treatment, in
agreement with results in animal models48,57.
The ‘hyperactive’ endocannabinoid system
In summary, animal studies suggest that the endocannabinoid system
is important in inducing food intake: it is transiently activated after
short-term fasting and/or exposure to palatable foods, thus inducing
appetite, reducing satiety and ultimately stimulating lipogenesis and
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Table 1 Multisite control of energy balance by the
endocannabinoid system.
The local endocannabinoid
system is:
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
Hypothalamus
Stimulated by fasting
Endocannabinoid activation
leads to:
Enhancement of orexin action
Stimulated by ghrelina
Downregulation of CRH
Inhibited by leptin
Inhibition of MC4R action
Increased appetite following
food deprivation
Mesolimbic
system
Stimulated by
palatable (high fat) food
Enhanced dopaminergic
signaling in NAc
Synergism with the opioid
system
Translation of motivation to
eat into action
Brainstem
Stimulated by fasting
Effects on nodose
ganglion and NTS neurons
Inhibited by CCK
Inhibition of satiety
and emesis
Gastrointestinal Stimulated by fasting
tract (duodenum)
Stimulation of TRPV1/CB1
neurons in the vagus nerve
Inhibition of satiety
White
adipose tissue
Hyperactivated by fat dieta
Downregulation of
adiponectina
Increased lipogenesis
Endocannabinoids and CB1 receptors are present in all central and peripheral sites
involved in the control of energy homeostasis. The external or internal stimuli that
regulate endocannabinoid or CB1 levels are listed for each site, together with the
most likely consequences. Evidence is emerging for a role of endocannabinoids in the
induction of fatty acid synthesis in the liver as well55. CCK, cholecystokinin; CRH,
corticotropin releasing hormone; MC4R, melanocortin receptor type 4; NTS, nucleus
tractus solitarius; TRPV1, transient receptor potential vanilloid 1 channel for capsaicin;
NAc, nucleus accumbens.
aData
for which there is only indirect experimental support.
decreasing energy expenditure (Table 1). This is consistent with the
emerging concept of elevated endocannabinoid levels after stressful
stimuli as a strategy to help organisms re-establish homeostasis11.
However, both preclinical and clinical studies clearly indicate that this
system also contributes to pathological conditions such as hyperphagia,
exaggerated fat accumulation and dyslipidemia, which are reduced by
pharmacologically decreasing the effects of endocannabinoids at CB1
receptors. A sustained hyperactivity of the endocannabinoid system,
limited to tissues controlling energy balance, thus may contribute to the
development of obesity and metabolic syndromes. Such hyperactivity
might be caused by high-fat diets and the subsequent increased availability of polyunsaturated fatty acid precursors for endocannabinoid
biosynthesis and it might be sustained by the resistance to leptin that
normally develops with obesity. Indeed, in newborn and adult rodents,
dietary ω6-polyunsaturated fatty acids increase brain endocannabinoid
levels, whereas prolonged semi-starvation or high dietary levels of ω3polyunsaturated fatty acids decrease them58–61. The hypothesis of a
locally hyperactive endocannabinoid system might explain why the
appropriate dose of a competitive CB1 antagonist can be used against
abdominal obesity and its consequences, seemingly without causing
major side effects.
This hypothesis is also supported by several other findings. First,
obese rats are more sensitive than lean rats to rimonabant48, although
the potential for accumulation of this lipophilic compound in the
adipose tissue may partly explain these differences as well as its longer-lasting peripheral actions. Second, adipocytes from obese rats and
588
differentiated adipocytes express more CB1 receptors than adipocytes
from lean rats or immature adipocytes54. Third, a high-fat diet results
in the enhancement of hepatic anandamide and CB1 levels55. Fourth,
significantly higher endocannabinoid concentrations are found in the
blood or visceral fat of obese humans (ref. 62 and R. Monteleone and
V.D.M., unpublished data). However, in vitro, CB1 antagonists act independently of enhanced endocannabinoid levels as inverse agonists, and
this property, although not normally observed in vivo, may underlie
part of their pharmacological actions63. Studies with inhibitors of endocannabinoid biosynthesis may help confirm the results obtained with
CB1 antagonists and prove conclusively the hypothesis of a hyperactive
endocannabinoid system as a factor contributing to obesity and related
disorders. Finally, based on the finding of altered endocannabinoid
levels in the blood of women with anorexia nervosa and binge eating
disorder, but not bulimia nervosa62, future investigations should also
address the possible role and regulation of the endocannabinoid system
in these eating disorders.
Note added in proof: A recent study has shown65 that overweight and
obesity in humans are associated with a potential genetic malfunctioning
of one of the endocannabinoid degrading enzymes, further substantiating the hypothesis of a hyperactive endocannabinoid system as a possible
cause of obesity.
COMPETING INTERESTS STATEMENT
The authors declare competing financial interests (see the Nature Neuroscience
website for details).
Received 10 January; accepted 21 February 2005
Published online at http://www.nature.com/natureneuroscience/
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